Compound {8 ({62 -hydroxyphenethyl)amino{9 ethyl thiocyanate and acid addition salts thereof

ABSTRACT

A method of preparing 2-(( Beta -hydroxy-phenethyl)amino)ethyl thiocyanate by contacting Alpha -phenyl-1-aziridineethanol with thiocyanic acid and products resulting, are described. The products of the process are useful as intermediates in preparing 2,3,5,6-tetrahydroimidazo(2,1-b)thiazoles useful as anthelmintics.

United States Patent Bullock [451 July 25, 1972 [54] COMPOUND [(B-I-IYDROXYPHENETHYDAMINO]ETHYL THIOCYANATE AND ACID ADDITION SALTSTHEREOF [72] Inventor: Milon Walker Bullock, Hopewell, NJ.

[73] Assignee: American Cyanamid Company, Stamford,

Conn.

June 11, 1970 |21| App]. No.: 45,571

I22| Filed:

Related U.S. Application Data [60] Continuation-in-part of Ser. No.669.715, Sept. 22, 1967, abandoned, which is a division of Ser. No.493,231, Oct. 5, 1965, abandoned.

[52] u.s.c| ..260/454,260/306.7,260/564E,

424/270 51 lnt.C1 ..C07cl6l/02 58 Field ofSearch ..260/454 [56]References Cited UNITED STATES PATENTS 3,437,666 4/1969 Pfugfclderet a1..260/454 OTHER PUBLICATIONS Primary E.\'aminerLewis Gotts AssistantExaminerG. Hollrah Attorney-Ernest Y. Miller [57] ABSTRACT A method ofpreparing 2-[(B-hydroxy-phenethyl)amino]ethy1 thiocyanate by contactinga-phenyl-l-aziridineethanol with thiocyanic acid and products resulting,are described. The products of the process are useful as intermediatesin preparing 2,3,5,6-tetrahydroimidazo[2,l-b]thiazo1es useful asanthelmintics.

6 Claims, No Drawings COMPOUND [(B-HYDROXYPHENETHYUAMINO] ETHYLTHIOCYANATE AND ACID ADDITION SALTS THEREOF This application is acontinuation-in-part of application, Ser. No. 669,715, filed Sept. 22,1967, now abandoned, which is a divisional of application, Ser. No.493,231, filed Oct. 5, 1965, now abandoned.

SUMMARY OF THE INVENTION This invention relates to intermediates in amethod of preparing substituted 2,3 ,5 ,6-tetrahydroimidazo[ 2, lb]thiazoles. More particularly, it relates to the preparation ofsubstituted 6-phenyl-2,3 ,5 ,6-tetrahydroimidazo[ 2, 1 b]thiazoles bythe use of novel intermediates, and methods of preparing the latter.

The new intermediates prepared by the process of the present inventioncan be illustrated by the following formula:

OH NEG-S (III) The acid addition salts such hydrochloride, hydrobromide, p-toluene sulfonate and the like are included within the presentinvention.

The intermediate directly convertible into the 2,3,5,6-

t etrahydroimidazo[2,1-b]thiazole described above is 3-(B- agents wellknown to those skilled in the art for transforming alcohols to halides.The reaction is usually carried out by mixing the intermediate with thehalogenating agent and heating at a temperature within range of to 120C. for 5 minutes to 4 hours.

The 2-imino-a-phenyl thiazolidineethanol is prepared by contacting ana-phenyl-l-aziridineethanol with at least 1 molar equivalent ofthiocyanic acid is usually prepared in situ by the acidification of anyammonium or metal thiocyanate salt. The reaction is carried out in alower alkyl alcohol of one to'four carbon atoms. It is not necessary toisolate the intermediate and heating the solution of the compound withan acid gives compound (11]). The 2-imino-a-phenyl-3-thiazolidineethanol can also be prepared by reactinga-phenyl-l-aziridineethanol with thiourea and a strong acid followed byheating.

The a-phenyl-l-aziridineethanol can be prepared by a reaction of styreneoxide with ethylenimine in an aqueous alkaline mixture as described byFunke et al. Bull. Soc. Chim., France, 1953(1201-3).

The process of the present invention starting with known reactants canbe illustrated by the following flowsheet;

"iii...

' wherein X is a cation.

from the corresponding 2-imino-a-phenyl thiazolidineethanol by reactionwith thionyl chloride, phosphorus trichloride, phosphorous tribromide,phosphorus oxychloride or other The preparation of Compound (I) has beendescribed by Funke et al. as hereinbefore indicated. The Compoundrepresented by formula (I) can be transformed into the Compound (II) byreaction of (I) with thiocyanic acid which can be prepared by theacidification of any ammonium or metal thiocyanate salt. When .thecompound (II) is heated with a strong acid, it is immediately convertedto the' 2- iminothiazoline (III). Compound (III) can also be prepared byreacting Compound (I) with thiourea anda strong acid which yields theCompound (Ila) which can be converted further to (III) by heating in asuitable reaction medium. The Compound (III) can be converted to theCompound (IV) by contacting (III) with thionyl chloride or other agentssuch as phosphorus trichloride which are known to transform alcohols tohalides. When the Compounds (IV) are contacted with a base and warmedslightly, it is transformed into the 2,3,5,6-tetrahydroimidazo[2,l-blthiazole free base represented by formula (V).If desired, the free base can be converted to salts, which arerepresented by formula (VI), by contacting the free base with an acid.

Compounds produced by the process of the present invention were testedby standard parasitological procedures for evaluating anthelminticefficacy, i.e., (1) in most cases the critical test in which the numberof worms eliminated in the feces following treatment is compared withthe total number of worms present, i.e., the sum of those eliminated andthose present at necropsy, and (2) the "controlled" test method in whichthe average numbers of worms present in treated animals is compared atnecropsy several days after treatment with the average number present insimilarly infected but untreated animals. Depending upon the hostspecies and the particular helminth studied the infections wereexperimentally induced or in some cases naturally acquired. The testsshowed that dl-2,3,5,6-tetrahydro 6-pheny1-imidazo[2,1-b]thiazolehydrochloride is highly active against a very broad spectrum of nematodeparasites of mammals and birds at low dosages, and by varied routes ofadministration. The following table gives illustrative representativeresults obtained in testing the above described imidazothiazole, and isnot intended to be limiting in regard to dose ranges, routes ofadministration, or species of nematodes. Data refer to adult helminthsunless otherwise indicated.

TABLE Host Doses Route of Approx. mgJkg. Adminaverage Species of Mouse(or other) istration efiicacy Adult Nematode l 00 Oral 100 S yphacia,

Gavage Arpiculuris 25 Oral 95-100 Nematospiroides Gavage dubius 20Subcut- 80 Nemarospiroides aneous dubius (0.1% in drug-diet 90 Ascarissuum feed) larvae 100 N. dubius Sheep 3.75-10 Oral 100 Haemon'chusDrench conrorrus 3.75-10 Oral: 85-99 Nematodirus sp.

Drench 5-10 Oral 90-100 Trichostrongylus Drench axei l 0 Oral 94Oslerlagia Drench circumcincta 1 5 Oral 100 Oslerlagia Drenchcircumcincta 7.5-1 0 Oral 95 Trichostrongylu:

Drench colubrij'ormis and T. vitrinu: 2.5-7.5 Subcut- 100 H.c.

aneous 5-7.5 Subcut- 95 On aneous 2.5-7.5 Subcut- 99 T.c. and T.v.

aneous I 57.5 Subcut- 97-100 Nemamdirus sp.

aneous Oral 99 11.0. larvae Drench 15 Oral 99 T.c. larvae Drench l5Subcut- 87 0.c. larvae aneous Cattle 2.51 0 Oral 100 Haemonchus placeiDrench 7.5- Oral 80-100 T. lzxei Drench 7.5-20 Oral 80-100 Osrertagi sp.

Drench 5-10 Oral 100 Coaperia sp.

Drench Cattle 7.5 Oral 100 Nemalodiru: :p.

Drench 5-10 Oral 100 Oesophagosmmum :p.

Drench 5-10 'lntra- 100 H.p. muscular or Subcutaneous 5-20 90+ T. axei5-20 90+ "Osrermgia sp. 5-10 I 100 "Cooperia sp. 5-10 lntra- 100Nemntodirus sp.

muscular 7 5-10 lntra- 100 Oes. sp.

. muscular 5-10 lntra- 100 Bunostomum sp.

muscular 7.5 lntraper- 100 H.p.

itoneal ss'sa 7.5 lntraper- 80 T. axei itoneal 7.5 lntraper- 90Oslertagia .rp.

itoneal 7.5 lntraper- 100 Cooperia sp.

itoneal 7.5 Inreaper- 100 Nemalodirur .rp.

itoneal 7.5 lntraper- 100 Bunaslomum sp.

itoneal Swine 5 Oral 100 Ascaris .ruum

capsule or feed 10 In drink 100 Arcaris suum ing water 2.5-10 In drink100 Melaslrongylus .rp. ing water or Oral Capsule 7 10-20 In drink 85Oesophagorlomum sp.

ing water (0.0125% In Feed 95 Arcaris .ruum in feed) Continlarvae uouslyDog 5 Subcut- 99 ancyloslama caninum aneous 10 Oral 90 Toxacara cam:

Capsule 10 Oral 100 Toxascaris Ieonina Capsule Chicken 80 in drink 90+Ascaridia galli ingwater larvae a. Unless otherwise indicated.

The following examples illustrate in detail the process of preparingsubstituted imidazothiazoles.

DETAILED DESCRIPTION EXAMPLE 1 dl a-Phenyll-Aziridineethanol To asolution of 43.0 grams (1.0 mole) of ethylene imine and 60.0 grams (0.5mole) of styrene oxide is added three drops of water and 0.2 grams ofpotassium hydroxide. The I mixture is heated at reflux for 1% hours.Distillation of the crude product gives 55.6 grams (68 percent) of thecrystalline produce. Recrystallization gives purea-phenyLlaziridineethanol with melting point 7476 C.

EXAMPLE 2 Distillation of the remaining oil gives an additional 307grams I of products, melting point 56-65 C., the total yield is 48 per'cent.

EXAMPLE 3 dl Z-Imino-a-Phenyl-3Thiazolidineethnaol Hydrochloride dl To asolution of 1.17 grams (0.012 mole) of potassium thiocyanate in 10 ml.of ethanol is added 0.011 mole of hydrogen v chloride in 3 ml. ofethanol. The mixture is warmed to 50 C., cooled, and the precipitatedpotassium chloride filtered off. The filtrate, which contains 0.01 1mole of thiocyanic acid, is added to a solution of 1.63 grams (0.01mole) of a-phenyl-laziridineethanol at a rate sufficient to maintain thereaction temperature at 3035 C. After the addition of the thiocyanicacid is complete, the intermediate product, d12-[(B-hydroxyphenethyl)amino] ethyl thiocyanate is treated with asolution of 0.015 mole of hydrogen chloride in 5 ml. of ethanol. Removalof the solvent at reduced pressure gives the rear-, ranged product,melting point l96-l99 C., in a percent yield. Recrystallization fromethanol provides the pure product, with melting point 198-200 C. Theabove reaction can be carried out in a lower alkyl alcohol having one tofour carbon atoms.

EXAMPLE 4 2-[(fi-HydroxyphenethyDAmino]Ethyl Thiocyanate Hydrochlorideand 2-lmino-a-Phenyl-3-Thiazolidine Ethanol Hydrochloride A mixture of8.11 g. (0.10 mole) sodium thiocyanate in about 150 ml. of isopropanolis acidified with 10 ml. (0.12 mole) of hydrochloric acid. A solution of18.0 g.(0.11 mole) a-phenyl-l-azirldineethanol in isopropanol is addedover a period of 10 minutes. An additional 8.3 ml. (0.1 mole)hydrochloride is added along with the aziridine. After a few minutes thesodium chloride is removed by filtration leaving a solution containing2-[(B-hydroxyphenethyl)aminolethylthiocyanate hydrochloride. Thesolution is heated for about an hour at about 50 C. and set aside toallow the rearrangement product, Z-imino-a-phenyl-3-thia2olidineethanolhydrochloride to crystallize. The product has a melting point 200204 C.

EXAMPLE 5 2-[(B-Hydroxyphenethyl)Amino]Ethyl Toluenesulfonate onQ-cncnmj HS CN CHr-QSOaH I @cnonmncmoms CN-CHvS 03H An ice-cold solutionof 0.0306 mole of thiocyanic acid is prepared from 1.56 g. (0.032equivalent) of concentrated sulfuric acid and 2.33 g. (0.0306 mole) ofammonium thio cyanate in ml. of ethanol and is then filtered to removeammonium sulfate. To this solution is added 11.60 g. (0.061 mole) ofp-toluenesulfonic acid. The solution is stirred at 0-5 C. while asolution of 5.00 g. (0.0306 mole) of a a-phenyl-laziridineethanol in ml.of ethanol is added dropwise over 45 minutes. After stirring for onehour at 05 C., and standing in the cold for 18 hours, the precipitate isfiltered, washed with ethanol, and dried to give 9.12 g. (75 percent) ofproduct, melting point 2l6-222 C. The infrared spectrum has a sharp peakat 2180 cm.- for the thiocyanate group and no absorption for C N.

Thiocyanate p- EXAMPLE 6 DL 2-lmino-a-Phenyl-3Thiazolidineethanolp-Toluene Sulfonate OH NH To an ice-cold stirred solution of 0.064 moleof thiocyanic acid in 40 ml. of ethanol is added, dropwise, a solutionof 3.26

g. (0.020 mole) of a-phenyl-l-aziridineethanol in 15 ml. of

ethanol over a period of 30 minutes. The solution is stirred at 0-5 for3 hours and then 20 ml. of 4.45 N hydrogen chloride in 2-propanol isadded. The cold mixture was filtered, washed with 2-propanol and driedto give 381 g. of crystalline product, melting point l28-l30 C. Theinfrared spectrum has a sharp band at 2180 cm. and no absorption for CN. When the product is heated in solution, it is rearranged as describedin Example 6.

EXAMPLE 8 dl 3-(fl-Chlorophenethyl)-2-lminothiazolidine Hydrochloride Toa solution of 2.25 grams (0.009 mole) of2-imino-aphenyl-3-thiazolidineethanol hydrochloride in 50 ml. ofchloroform is added 3 ml. of thionyl chloride. The mixture is refluxedfor 30 minutes, and the solvent removed under pressure to give 1.93grams of solid product.

EXAMPLE 9 dl 6-Phenyl-2,3,5 ,6-Tetrahydroimidazo[ 2, l -b]Thiazole To asolution of 1.30 grams (0.005 mole) of 3-(B-chlorophenethyl)-2-iminothiazolidine hydrochloride in 50 ml. ofchloroform is added a solution of 2.76 grams of potassium carbonate in10 ml. of water. The mixture is heated at reflux for one hour, cooled,and the layers separated. The organic layer is washed with water anddried over potassium carbonate. Removal of the solvent under reducedpressure gives 1.0 grams of impure solid. Crystallization from ethergives the pure product, melting point 9092 C.

EXAMPLE l0 dl 6-Phenyl-2,3 ,5 ,6-tetrahydroimidazo[ 2, 1 -b Chloride Toa solution of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,lb]thiazole inisopropanol is added a solution of hydrogen chloride in isopropanol. Theprecipitated hydrochloride is filtered, and washed consecutively withethanol and ether. The crystalline product has melting point 26l262 C.with decomposition.

EXAMPLE 11 (ll 2-lmino-a-phenyl-3-thiazolidineethanol Hydrochloride Whena-phenyl-l-aziridineethanol is mixed with a stoichometric quantity ofthiourea in the presence of hydrochloric acid the product obtained is d12{2[(B-hydrox yphenyl-ethyl)amino]ethyl }-2-thiopseudourea. The latterproduct on heating produces the product.

| Q-CHCHgNHCHzCHfiON l i T mom-$11G EXAMPLE 7 2-[(B-Hydroxyphenethyl)Amino]Ethyl Hydrochlride Thiocyanate cHaQsom EXAMPLE12 d1 Z-Phenyl 2,3,5,6-Tetrahydroimidazo[2,l-b]Thiazolium Chloride Onegram (0.036 mole) of 3-(fi-chlorophenethyl)-2- iminothiazolidinehydrochloride is partitioned between 50 ml. of ethylacetate and asolution of 2.34 g. (0.017 moles) of potassium carbonate in 32 ml. ofwater. The ethylacetate layer is separated and heated at refluxtemperature for 2% hours. The precipitate of 6-phenyl2,3,5,6-tetrahydroimidazol2,1- b]thiazolium chloride is collected byfiltration and recrystallized from absolute ethanol to yield 0.3 g. ofpure product,

melting point 257259 C.

I claim:

1. The compound dl-[(B-hydroxyphenethyl)aminolethyl thiocyanate, and itsacid addition salts selected from the group consisting of hydrochloride,hydrobromide and p-toluenesulfonate.

2. The compound according to claim 1, in which the acid addition salt ishydrochloride.

3. The compound according to claim 1, in which the acid addition salt isp-toluenesulfonate.

4. A solution of d] 2-[(B-hydroxyphenethyl)aminole thylthiocyanate andits acid addition salts selected from the group consisting ofhydrochloride, hydrobromide and p- 5 toluenesulfonate in a lower alkylalcohol solvent having one to four carbon atoms.

5. A solution according to claim 4, wherein the solvent is ethanol.

6. A solution according to claim 4, wherein the solvent is isopropanol.

i I! II t i

2. The compound according to claim 1, in which the acid addition salt ishydrochloride.
 3. The compound according to claim 1, in which the acidaddition salt is p-toluenesulfonate.
 4. A solution of dl 2-(( Beta-hydroxyphenethyl)amino)ethylthiocyanate and its acid addition saltsselected from the group consisting of hydrochloride, hydrobromide andp-toluenesulfonate in a lower alkyl alcohol solvent having one to fourcarbon atoms.
 5. A solution according to claim 4, wherein the solvent isethanol.
 6. A solution according to claim 4, wherein the solvent isisopropanol.